This application addresses broad needs for comparative effectiveness research and proposes to conduct and analytic epidemiologic studies of retrospective cohort design, to assess the benefits and harms of preventive or therapeutic interventions in "real world" settings for patients who have multiple chronic co morbid conditions. It proposes research on chronic kidney disease (CKD) in diabetes patients and its progression to end stage renal disease (ESRD), conditions that are devastating and increasingly prevalent, with high mortality and high direct costs of care. Although a number of treatments are widely recommended for slowing progression of CKD and reducing risks of associated cardiovascular disease (CVD), ESRD, and mortality, there is little experimental evidence to support these recommendations and there have been few trials comparing drugs within classes in terms of effectiveness and safety. Such trials are unlikely to be done in the near future and much can be learned from careful observational studies of existing patient data to identify the most safe and effective treatments. We propose to conduct such studies in the diabetes patient population served by the Veterans Health Administration (VA), the largest sample of older adults in an integrated health care system in the U.S. with comprehensive electronic medical records. These patients have high prevalence of CKD and other morbidities, and represent those who are often excluded from clinical trials. We have shown in our previous work that large, rigorous, longitudinal studies can be done in the VA and we have developed and evaluated methodologies for such research. We now propose to study complex diabetes patients with CKD and other co-morbidities in order to evaluate comparative effectiveness and safety in slowing the progression of kidney disease (decline in estimated glomerular filtration rate (eGFR), transition in CKD stage, transition to ESRD), reducing risks of other outcomes (CVD events, mortality), and having low associated risks of medication-related adverse renal outcomes (acute kidney injury, hyperkalemia) and other adverse events (hypoglycemia, angioedema, falls). Class-to class and drug-to-drug comparisons will be made within the following classes or groups of medications recommended for treating CKD: angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and HMGcoA reductase inhibitors (statins). Samples and exposure groups will be selected carefully to replicate common clinical decisions in treatment and up to 11 years of national data will be used with application of rigorous epidemiologic methods to reduce potential bias and provide valid and meaningful results. This research represents a real opportunity to better understand benefits and risks associated with treatments for CKD in complex diabetes patients and application of its findings should result in safer and more effective prescribing practices. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a common, debilitating condition in older people with diabetes that is associated with premature mortality and high costs of care. A number of medication classes have been recommended for preventing or slowing progression of the disease but there is little evidence to support these recommendations in complex diabetic patients and more information is needed on which drugs are most safe and effective. We propose to study the comparative effective and safety of these drugs in complex diabetes patients with chronic kidney disease who receive care at the Veterans Health Administration. Patients will be studied over an eleven year period in order to determine which drugs are the most beneficial and safe. This information should guide future prescribing practices and reduce the burden of this disease in our aging population.